PKCα Deficiency in Mice Is Associated with Pulmonary Vascular Hyperresponsiveness to Thromboxane A2 and Increased Thromboxane Receptor Expression.

Abstract

Pulmonary vascular hyperresponsiveness is a main characteristic of pulmonary arterial hypertension (PAH). In PAH patients, elevated levels of the vasoconstrictors thromboxane A2 (TXA2), endothelin (ET)-1 and serotonin further contribute to pulmonary hypertension. Protein kinase C (PKC) isozyme alpha (PKCα) is a known modulator of smooth muscle cell contraction. However, the effects of PKCα deficiency on pulmonary vasoconstriction have not yet been investigated. Thus, the role of PKCα in pulmonary vascular responsiveness to the TXA2 analog U46619, ET-1, serotonin and acute hypoxia was investigated in isolated lungs of PKCα-/- mice and corresponding wild-type mice, with or without prior administration of the PKC inhibitor bisindolylmaleimide I or Gö6976. mRNA was quantified from microdissected intrapulmonary arteries. We found that broad-spectrum PKC inhibition reduced pulmonary vascular responsiveness to ET-1 and acute hypoxia and, by trend, to U46619. Analogously, selective inhibition of conventional PKC isozymes or PKCα deficiency reduced ET-1-evoked pulmonary vasoconstriction. The pulmonary vasopressor response to serotonin was unaffected by either broad PKC inhibition or PKCα deficiency. Surprisingly, PKCα-/- mice showed pulmonary vascular hyperresponsiveness to U46619 and increased TXA2 receptor (TP receptor) expression in the intrapulmonary arteries. To conclude, PKCα regulates ET-1-induced pulmonary vasoconstriction. However, PKCα deficiency leads to pulmonary vascular hyperresponsiveness to TXA2, possibly via increased pulmonary arterial TP receptor expression.

• Authors: Christoph Tabeling, Elena Noe, Jan Naujoks, Jan-Moritz Doehn, Stefan Hippenstiel, Bastian Opitz, Norbert Suttorp, Robert Klopfleisch, Martin Witzenrath
• Journal: Journal of vascular research (J Vasc Res) Vol. 52 Issue 4 Pg. 279-88 ( 2015) ISSN: 1423-0135 [Electronic] Switzerland
• PMID: 26890419 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 S. Karger AG, Basel.

Chemical References

• Endothelin-1
• Protein Kinase Inhibitors
• Receptors, Thromboxane A2, Prostaglandin H2
• Vasoconstrictor Agents
• Serotonin
• Thromboxane A2
• 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
• Prkca protein, mouse
• Protein Kinase C-alpha

Topics

• 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid (pharmacology)
• Animals
• Dose-Response Relationship, Drug
• Endothelin-1 (pharmacology)
• Female
• Genotype
• Mice, 129 Strain
• Mice, Knockout
• Phenotype
• Protein Kinase C-alpha (antagonists & inhibitors, deficiency, genetics)
• Protein Kinase Inhibitors (pharmacology)
• Pulmonary Artery (drug effects, enzymology)
• Receptors, Thromboxane A2, Prostaglandin H2 (agonists, genetics, metabolism)
• Serotonin (pharmacology)
• Thromboxane A2 (pharmacology)
• Up-Regulation
• Vasoconstriction (drug effects)
• Vasoconstrictor Agents (pharmacology)